Muscular dystrophies (MD) are progressive inherited neuromuscular disorders that are characterized by muscle wasting and weakness (Emery (2002) The Lancet, 359:687-695). Many forms of muscular dystrophies are fatal and currently incurable.
Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular disease. The disease is caused by mutations in the DMD gene coding for dystrophin. Alteration or absence of this protein results in abnormal sarcolemmal membrane tearing. An abnormal variation in diameter of muscle fibers (atrophic and hypertrophic fibers) in proximal muscles and ongoing muscle damage are hallmarks of the disease. Damaged muscle releases the intracellular enzyme creatine kinase (CK). As a result, the serum CK levels in DMD patients are characteristically high (up to 10 times the normal). The pathophysiologic cascade is compounded by tissue inflammation, myofiber necrosis and replacement of muscle with fibrofatty tissue.
Another allelic variant of the DMD gene causes a milder form of MD known as Becker muscular dystrophy (BMD). BMD is clinically similar to DMD but the onset of symptoms occurs later in life.
Many pharmacological agents have been tried in MD but none has proved effective in arresting the course of the disease. The current modality of treatment is still in the realm of physical medicine and rehabilitation.
A number of trials using corticosteroids (e.g., prednisone and/or its derivatives) have demonstrated improvement in individuals with MD, particularly in the short-term. Although the exact mechanism by which corticosteroids alleviate the disease phenotype is unclear, corticosteroids are thought to act by reducing inflammation, suppressing the immune system, improving calcium homeostasis, upregulating expression of compensatory proteins, and increasing myoblast proliferation (Khurana et al. (2003) Nat. Rev. Drug Discovery 2:279-386). However, corticosteroids administered over time can induce muscle atrophy, which primarily affects proximal muscles—the very same muscles that are affected in DMD and BMD. The corticosteroid-induced muscle and other side effects may limit the long-term effectiveness of corticosteroid therapy.
GDF-8 is a member of the TGF-β superfamily and functions as a negative regulator of muscle growth. Similarly to other members of the superfamily, GDF-8 is synthesized as a precursor molecule, but prior to secretion, it is cleaved into the N-terminal inhibitory propeptide and C-terminal the active mature GDF-8. Propeptide may remain bound to GDF-8 thereby inhibiting the biological activity of mature GDF-8. Propeptide must dissociate from the complex for GDF-8 to bind to activin type II receptor (ActRIIB). Upon binding, ActRIIB initiates a signaling cascade, ultimately leading to the inhibition of myoblast progression. Antibody-mediated inhibition of GDF-8 in vivo has been shown to significantly increase skeletal muscle size in normal adult mice (Whittemore et al. (2003) BBRC, 300:965-971) and to alleviate the dystrophic phenotype in the mdx mouse model of DMD (Bogdanovich et al. (2002) Nature, 420(28):418-421).